Ingestible hydrophilic polymeric amines useful for lowering blood cholesterol

ABSTRACT

The invention is concerned with novel ingestible cross-linked homopolymers having functional groups consisting of linear or branched amines, of the formula: ##STR1## and their pharmaceutically acceptable salts of the formulae: ##STR2## wherein P represents a hydrophilic, cross-linked and non-digestible homopolymer backbone; R is a hydrogen atom or a lower alkyl radical; X -  is a pharmaceutically acceptable anion; m is an integer varying from 1 to 10 inclusive; and n, o and p are, independently, integers varying from 2 to 12 inclusive. The amine functionalized and cross-linked homopolymers of the invention are highly efficient adsorbents for bile acids and salts and can thus be used for reducing hypercholesterolemia in affected humans.

The present invention relates to novel ingestible amine functionalizedand cross-linked homopolymers which are useful as adsorbents for salts.More particularly, the invention is directed toward the treatment ofhypercholesterolemia by removing through adsorption the bile acids andsalts from the small intestine, thereby increasing the catabolism ofcholesterol in the liver with a concomitant decrease in the bloodcholesterol level.

Elevation of the blood cholesterol, hypercholesterolemia, is widelyconsidered as a major risk factor for the development of atherosclerosisand cardiovascular diseases. It is presently the leading cause of deathof adults in most of the developed countries. Over the last few decades,researchers have focussed their attention on lowering the cholesterollevel in the blood to reduce the risk of cardiovascular diseases. Thiscan be achieved with limited success by reducing in the cholesterolintake from food sources and accelerating the elimination of cholesterolfrom the human body, although genetic factors can also be important. Insevere cases, the disease can be treated clinically by oral drugs,surgery, hemoperfusion or a combination of these treatments.

Biologically, cholesterol is eliminated from the human body byconversion to bile acids and excretion as neutral steroids. Bile acidsare synthesized daily from cholesterol in the liver and enter the bileas glycine and taurine conjugates. They are released in salt form withbile during digestion. Bile salts are mostly reabsorbed in the ileumwith only about 1% loss per cycle, complexed with proteins and returnedto the liver through hepatic portal veins. This small loss of bile saltsrepresents a major route for the elimination of cholesterol from thebody.

The available prescription drugs interrupt either the biosynthesis ofcholesterol in the body or the enterohepatic circulation of bile salts.Some of the inhibitors for the biosynthesis of cholesterol, such aslovastatin (Mevinolin), are reported to be significantly effective.Their clinical usefulness is limited however, due to some of theiruntoward side effects. Medicines acting as adsorbents, such ascholestyramine and colestipol, bind bile salts in the small intestine,thus preventing the reabsorption of bile salts. The fecal excretion ofbile salts is enhanced under the effect of cholestyramine and,therefore, the conversion of cholesterol to bile acids is accelerated tomaintain the bile pool. However, both cholestyramine and colestipol havemajor side effects which include the bad taste and the dryness ofcholestyramine, low adsorption capacity of colestipol, and their poorbiological compatibilities.

Cholestyramine, the most widely used adsorbent for bile salts, is acopolymer of polystyrene and divinylbenzene with quaternary ammoniumgroups as functional groups. Being a typical strongly basic ionexchanger, its counterions of the quaternary ammonium, usually chlorideions, are exchanged with bile salt anions during the binding. Thehydrophobic nature of the polymer backbone results in its poorbiocompatibility. As a consequence, adverse side effects have beenexperienced by hypercholesterolemic patients. The drug has to be takenin large dosage and may cause stomach discomfort to patients.

It is therefore an object of the present invention to overcome the abovedrawbacks and to provide novel bile salt adsorbents with high adsorptioncapacity, good biocompatibility and improved taste.

In accordance with the invention, there is provided a novel cross-linkedhomopolymer having functional groups consisting of linear or branchedamines of the formula: ##STR3## as well as the pharmaceuticallyacceptable salts thereof having the formulae: ##STR4## wherein:

P represents a hydrophilic, cross-linked and non-digestible homopolymerbackbone;

R is a hydrogen atom or a lower alkyl radical;

X⁻ is a pharmaceutically acceptable anion;

m is an integer varying from 1 to 10 inclusive; and

n, o and p are, independently, integers varying from 2 to 12 inclusive.

It has been found quite unexpectedly that the above polymeric compoundsexhibit increased hydrophilicity and are highly efficient adsorbents forcholic acid and glycocholic acid as well as other bile acids, such aschenodeoxycholic acid, lithocholic acid, deoxycholic acid andtaurocholic acid. The significance of the bile acid adsorption isrelated to the lowering of serum cholesterol. As it is known,cholesterol is a major and probably the sole precursor of bile acidsduring normal digestion, bile acids are secreted via the bile from theliver and the gallbladder into the intestine. Bile acids emulsify thefat and lipid materials present in the foods, thus facilitatingadsorption. A major portion of bile acids secreted is reabsorded fromthe intestines and returned via the portal circulation of the liver,thus completing the enterohepatic cycle. The binding of bile acids inthe intestines onto an insoluble adsorbent that is excreted in the fecesresults in partial removal of bile acids from the enterohepaticcirculation, preventing their readsorption. The increased fecal loss ofbile acids leads to an increased oxidation of cholesterol to bile acids,a decrease in beta lipoprotein or low density lipoprotein serum levels,and a decrease in serum cholesterol level. Thus, the compounds of theinvention can be used for reducing hypercholesterolemia in affectedhumans.

Accordingly, the present invention also provides, in a further aspectthereof, a method of treating hypercholesterolemia in an affected human,which comprises administering to the affected human an effective amountof a bile salt adsorbent consisting of an amine functionalized andcross-linked homopolymer as defined above.

According to yet another aspect of the invention, there is provided apharmaceutical composition for the treatment of hypercholesterolemia,which comprises as active ingredient an amine functionalized andcross-linked homopolymer as defined above, together with apharmaceutically acceptable carrier therefor.

The polymer backbone to which the amino groups are chemically bondedmust be hydrophilic so as to swell in an aqueous medium. This ensuresgood contact with the medium and also opens the pores in the polymer sothat there is good access to all of the functional groups. The polymerbackbone must also be cross-linked to prevent the adsorbent fromdiffusing from the digestive tract, as well as non-digestable to preventthe adsorbent from being broken down and absorbed into the body. It ispreferably porous to permit diffusion of the bile salts which are to besequestered, thereby improving adsorption capacity.

A preferred polymer resin for use as backbone to which the amino groupscan be attached is a porous, cross-linked polymethylacrylate resin. Sucha resin is advantageously prepared by polymerizing methyl acrylate inthe presence of two cross-linking agents used in a ratio of 1:1.

Particularly preferred amine-containing resins according to theinvention are the homopolymers functionalized with linear amines offormula (Ia) and their protonated and quaternized derivatives of formula(Ic), in which R is a hydrogen atom or a methyl radical, m is 1, 2 or 3,n is 2 or 3, P represents a polyacrylamide resin and X⁻ is apharmaceutically acceptable anion such as Cl⁻, I⁻ or OH⁻.

Amongst the homopolymers functionalized with branched amines of formula(Ib) and their protonated and quaternized derivatives of formula (Id),the preferred compounds are those in which R is a hydrogen atom or amethyl radical, m is 1, n, o and p are each 2, P represents apolyacrylamide resin and X⁻ is a pharmaceutically acceptable anion.

The amine-containing resins according to the invention not only exhibithigh adsorption capacity but also high water-swellability, which renderthem suitable for clinical application.

Further features and advantages of the invention will become morereadily apparent from the following non-limiting examples and theaccompanying drawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 show the adsorption isotherms of compounds according tothe invention for sodium glycocholate in 0.0025M, pH 7.1 Tris buffer,compared with the adsorption isotherms of cholestyramine and colestipol(used as reference adsorbents);

FIG. 3 shows bile salt adsorption isotherms in simulated small intestinecontents; and

FIG. 4 shows bile salt adsorption isotherms in an extract from pig smallintestine.

1. PREPARATION OF POLYMER BACKBONE

A suitable carrier resin was synthesized by polymerizing methyl acrylatein the presence of cross-linking agents to form a porous, cross-linkedpolymethylacrylate (PMA) resin.

The polymerization was carried out in a 1000 ml 3-necked flask equippedwith a mechanical stirrer and a condenser. Into the flask, 25 grams ofNaCl and 480 ml distilled water were added. The solution was stirreduntil all of the NaCl has been dissolved. The temperature of the waterbath was set at 50° C. 120 ml of 2% polyvinyl alcohol (PVA) solution wasadded and the solution was mixed. The position of the stirring blade wasadjusted so that the top of the blade was at the surface of the waterphase.

In a separate beaker, 94 grams of methyl acrylate, 3.0 grams of each ofthe cross-linking agents, divinyl benzene andtriallyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione, and 1.4 grams ofbenzoyl peroxide were added. The benzoyl peroxide was allowed todissolve completely Then 20-25 grams of butyl ether was added and thecontents were well mixed.

This mixture was then added to the contents of the 1000 ml flask, andformed an oil phase. Stirring was then commenced with the speed beingcontrolled so as to yield the appropriate bead size for the carrierresin.

The temperature of the water bath was then increased slowly (8° C./ hr)until it reached 60° C., and then increased more slowly (4° C./ hr) to68° C. The system was maintained at this temperature for 24 hours,following which the polymerization was continued for 24 hours at 80° C.and another 24 hours at 95° C.

The product was cooled and washed repeatedly with warm water to removethe PVA. It was then washed by refluxing methanol for 24 hours to removebutyl ether and soluble polymer species. The carrier resin thus obtainedwas ready for functionalization.

2. FUNCTIONALIZATION OF POLYMER BACKBONE

A 200 ml 3-necked flask equipped with a mechanical stirrer, a condenser,a thermometer, CaCO₃ drying tube was immersed in an oil bath. 5 grams ofPMA and 100 ml of an alkyldiamine were added into the flask and stirredfor one hour at room temperature. The temperature was then increased to50° C. and was maintained for 3 hours. Thereafter it was increased to120° C., and maintained at this temperature for 4 days. Theamine-containing resin thus obtained was repeatedly washed withmethanol, and then with distilled water. It was finally dried undervacuum.

3. QUATERNIZATION OF THE AMINE-CONTAINING RESINS

A 500 ml 3-necked flask equipped with mechanical stirrer, a condenser towhich a CaCO₃ drying tube was attached, a thermometer was immersed in anoil bath. 5 grams of amine-containing resin prepared above, 25 grams ofKHCO₃ and 150 ml methanol were added into the flask. After 2 hours ofstirring at 35° C., 80 ml of methyl iodide was added. The reaction wasmaintained for 4 days in the dark. The final product was repeatedlywashed with methanol, with distilled water, with concentrated NaClsolution, and eventually with water.

4. PROTONATION OF THE AMINE-CONTAINING RESINS

The amine-containing resins were treated with dilute hydrochloric acidsolution at room temperature to convert the free amine groups topositively charged organic ammonium groups. This can be done either in acolumn where dilute HCl passes through the column until the protonationis complete, or simply in a container where an excess amount ofhydrochloric acid is in contact with the resin (standing or shaking).Then the excess hydrochloric acid was washed away with a large amount ofdistilled water until the resin is neutral.

5. CHARACTERIZATION OF THE ADSORBENTS

The products were characterized both qualitatively by infraredspectroscopy and quantitatively by acid-base back titration. IR resultsproved that the ester groups in the former PMA backbone had beenconverted to amide groups and the amine-containing small molecules havebeen chemically attached to the polymer backbone as expected. Fromacid-base back titration, it was found that all of the products werenitrogen rich materials and that they had subtitutions (free base orprotonated or quaternized nitrogen) of about 2-8 mmol/g.

6. ADSORPTION STUDIES

(a). Adsorption studies in Tris buffer

Tris(hydroxymethyl)-aminomethane (Aldrich) and 1.000N standard HClsolution were used to prepare a buffered solution with ionic strength0.0025M and pH 7.1. With this buffer, bile salt solution withconcentration about 50 mg/dl was prepared and was used directly. Intobottles of different sizes (2-100 ml), about 5-15 mg of the resin to betested was weighed. Then different volumes of bile salt solution (1-50ml) were added into the bottles. By changing the volumes of the bilesalt solution added, a whole range of bile salt equilibriumconcentrations was easily reached. They were shaken at room temperature(15°-25° C.) for more than 2 hours. Then they were filtered and theclear solutions were analyzed by High Performance Liquid Chromatography(HPLC) for which a perfect linear calibration curve was obtained underthe used experimental conditions.

(b). Adsorption Studies in Simulated Intestine Contents and ExtractedPig Small Intestine

The simulated small intestine solution with bile salt concentrationabout 100 mg/dl was prepared by dissolving each capsule of Cotazym-65B(Organon) in 60 ml distilled water. Pig small intestine was collectedfrom freshly killed pigs. The contents of the small intestine weresqueezed into a container and filtered to obtain a milky fluid for theadsorption studies. The pH of the above two was measured to be close to7.0. About 3-5 mg of the resin was weighed into bottles of differentsizes and each was pre-swollen with one-drop of distilled water.Different volumes of the solution were added into the resin bottles.They were shaken at 37° C. for 4 hours. 200 ul of each fluid wascentrifuged. The upper clear solution was diluted 50 times and wasanalyzed by fluorescence.

EXAMPLE 1

A hydrophilic amine-containing resin was prepared as described above bygrafting onto the cross-linked polymethylacrylate backbone ethylenediamine and was then converted to the hydrochloric form by washing withdilute aqueous HCl. This material, designated "unquaternized resin 1",was stirred or shaken with a Na⁺ -glycocholate solution in Tris bufferat initial concentration of 30-50 mg/dl for more than 2 hours. Theamount of Na⁺ -glycocholate adsorbed was measured by HPLC as describedabove. The adsorption isotherm is shown in FIG. 1. At an equilibriumconcentration of 0.4 mM, this resin adsorbed 4.5 mmol of Na⁺-glycocholate per gram of resin.

EXAMPLE 2

Example 1 was repeated except that diethylenetriamine instead ofethylene diamine was grafted onto the polymethylacrylate backbone. Theproduct obtained, designated "unquaternized resin 2", adsorbed 3.2 mmolof Na⁺ -glycocholate per gram of resin at an equilibrium concentrationof 0.4 mM. The adsorption isotherm is shown in FIG. 2.

EXAMPLE 3

Example 1 was repeated except that 1,4-diaminobutane instead of ethylenediamine was grafted onto the polymethylacrylate backbone. The productobtained, designated "unquaternized resin 3", adsorbed 1.5 mmol of Na⁺-glycocholate per gram of resin at an equilibrium concentration of 0.4mM. The adsorption isotherm is shown in FIG. 2.

EXAMPLE 4

Example 1 was repeated except that 1,6-hexanediamine instead of ethylenediamine was grafted onto the polymethylacrylate backbone. The productobtained, designated "unquaternized resin 4", adsorbed 2.0 mmol of Na⁺-glycocholate per gram of resin at an equilibrium concentration of 0.4mM. The adsorption isotherm is shown in FIG. 2.

EXAMPLE 5

Example 1 was repeated except that 1,3-diaminopropane instead ofethylene diamine was grafted onto the polymethylacrylate backbone. Theproduct obtained, designated "unquaternized resin 5", adsorbed 4.2 mmolof Na⁺ -glycocholate per gram of resin at an equilibrium concentrationof 0.4 mM. The adsorption isotherm is shown in FIG. 2.

EXAMPLE 6

Example 1 was repeated except than 1,12-diaminododecane instead ofethylene diamine was grafted onto the polymethylacrylate backbone. Theproduct obtained, designated "unquaternized resin 6", adsorbed 1.2 mmolof Na⁺ -glycocholate per gram of resin at an equilibrium concentrationof 0.4 mM. The adsorption isotherm is shown in FIG. 2.

EXAMPLE 7

Example 1 was repeated except that the amine-containing resin wasquaternized with methyl iodide and then was converted to chloride formby washing with concentrated sodium chloride solution. The productobtained, designated "quaternized resin 1", adsorbed 1.7 mmol of Na⁺-glycocholate per gram of resin at an equilibrium concentration of 0.4mM. The adsorption isotherm is shown in FIG. 1.

EXAMPLE 8

Example 2 was repeated except that the amine-containing resin asquaternized and converted in the manner described in Example 7. Theproduct obtained, designated "quaternized resin 2", adsorbed 3.0 mmol ofNa⁺ -glycocholate per gram of resin at an equilibrium concentration of0.4 mM. The adsorption isotherm is shown in FIG. 1.

EXAMPLE 9

Example 1 was repeated except that the triethylenetetramine instead ofethylene diamine was grafted onto the polymethylacrylate backbone andthat the amine-containing resin was quaternized and converted the waymentioned in Example 7. The product obtained, designated "quaternizedresin 7", adsorbed 3.2 mmol of Na⁺ -glycocholate per gram of resin at anequilibrium concentration of 0.4 mM. The adsorption isotherm is shown inFIG. 1.

EXAMPLE 10

Example 1 was repeated except that tris(2-aminoethyl) amine instead ofethylene diamine was grafted onto the polymethylacrylate backbone. Theproduct obtained, designated "unquaternized resin 8", adsorbed 2.2 mmolof Na⁺ -glycocholate per gram of resin at an equilibrium concentrationof 0.4 mM. The adsorption isotherm is shown in FIG. 2.

EXAMPLE 11

The amine-containing resin of Example 2, designated "unquaternized resin2", was stirred or shaken with a simulated small intestine solution asdefined above for 4 hours at 37° C. and at Na⁺ -glycocholate initialconcentration of about 100 mg/dl. The amount of Na³⁰ glycocholateadsorbed by this resin, as measured by fluorescence, was 0.7 mmol of Na⁺-glycocholate per gram of resin at an equilibrium concentration of 1.0mM. The adsorption isotherm is shown in FIG. 3.

EXAMPLE 12

The amine-containing resin of Example 8, designated "quaternized resin2", was stirred or shaken with a simulated small intestine solution asdefined above for 4 hours at 37° C. and at Na⁺ -glycocholate initialconcentration of about 100 mg/dl. The amount of Na⁺ -glycocholateadsorbed by this resin, as measured by fluorescence, was 1.8 mmol of Na⁺-glycocholate per gram of resin at an equilibrium concentration of 1.0mM. The adsorption isotherm is shown in FIG. 3.

EXAMPLE 13

The amine-containing resins of Examples 2 and 8, designated"unquaternized resin 2" and "quaternized resin 2", respectively, werestirred or shaken with extracted pig small intestine as defined abovefor 4 hours at 37° C. and at a bile salt initial concentration of about150 mg/dl. Good adsorption capacities were manifested in both cases atconcentration above 2 mM/L. The adsorption isotherms are shown in FIG.4.

The adsorption capacities of the amino-containing resins prepared inExamples 1 through 10 are summarized in the following Table:

                  TABLE 1                                                         ______________________________________                                                                           Adsorption                                 Ex.  Product                       Capacity                                   No.  Designation                                                                             Structure           (*)                                        ______________________________________                                        1    Unquater- P(CH.sub.2).sub.2 N.sup.+ H.sub.3 Cl.sup.-                                                        4.5                                             nized                                                                         Resin 1                                                                  2    Unquater- P[(CH.sub.2).sub.2 N.sup.+ H.sub.2 Cl.sup.- ].sub.2                                               3.2                                             nized                                                                         Resin 2                                                                  3    Unquater- P(CH.sub.2).sub.4 N.sup.+ H.sub.3 Cl.sup.-                                                        1.5                                             nized                                                                         Resin 3                                                                  4    Unquater- P(CH.sub.2).sub.6 N.sup.+ H.sub.3 Cl.sup.-                                                        2.0                                             nized                                                                         Resin 4                                                                  5    Unquater- P(CH.sub.2).sub.3 N.sup.+ H.sub.3 Cl.sup.-                                                        4.2                                             nized                                                                         Resin 5                                                                  6    Unquater- P(CH.sub.2).sub.12 N.sup.+ H.sub.3 Cl.sup.-                                                       1.2                                             nized                                                                         Resin 6                                                                  7    Quater-   P(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.3 Cl.sup.-                                               1.7                                             nized                                                                         Resin 1                                                                  8    Quater-   P[(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2 Cl.sup.-                          ].sub.2 CH.sub. 3   3.0                                             nized                                                                         Resin 2                                                                  9    Quater-   P[(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2 Cl.sup.-                          ].sub.3 CH.sub.3    3.2                                             nized                                                                         Resin 7                                                                  10   Unquater- nized Resin 8                                                                  ##STR5##           2.2                                        ______________________________________                                         (*) mmol of sodium glycocholate adsorbed per gram of resin                    (at an equilibrium concentration of 0.4 mM).                             

As may be seen from FIGS. 1 and 2, the shapes of the isotherms arestrongly dependent on the structure (hydrophobicity) of the sorbent. Asthe ionic strength of the buffer increases, the adsorption affinitydecreases markedly. The adsorption by the unquaternized sorbents isstrongly dependent on pH and is favoured by an increase in temperatureand smaller particle size. It is also apparent that the preferredamine-containing resins of the invention have higher adsorptioncapacities, in vitro, than the commonly used cholestyramine andcolestipol.

For any medical applications, especially by oral administration, thewater-swellability of the material is often considered as a majorevaluation parameter because most of the human fluids have high watercontents. Generally, the more water-swellable the polymer material is,the more biocompatible it will be.

The measurements of the water-swellability were done in several 10 mlgraduate cylinders. About 0.5 gram of the resin was weighed and put intothe cylinder. After it was tapped for a while, the initial reading,volume of the resin, was taken and recorded. Then enough distilled waterwas added to the cylinder and let it stand for at least 24 hours. Thefinal volume was taken. The resin was separated from the unabsorbedwater. The swollen resin was weighed again. The swellability and thewater content (adsorption capacity of water) were calculated, which wereexpressed as percentage of the volume change over the initial volume.

    Swellability=(V.sub.p -V.sub.o)/V.sub.o ×100%

    Water content=(W.sub.p -W.sub.o)/W.sub.o ×100%

where:

V_(o) and W_(o) are the original values

V_(p) and W_(p) are the values after swelling.

The results from these measurements are listed in the following Table:

                  TABLE 2                                                         ______________________________________                                        Product       H.sub.2 O swellability                                                                     H.sub.2 O content                                  ______________________________________                                        Unquaternized 500%         560%                                               Resin 1                                                                       Unquaternized 220%         240%                                               Resin 2                                                                       Unquaternized 162%         220%                                               Resin 4                                                                       Quaternized   260%         460%                                               Resin 1                                                                       Quaternized   338%         320%                                               Resin 2                                                                       Quaternized   150%         260%                                               Resin 4                                                                       ______________________________________                                    

It can be seen that the above materials are extremely water-swellable.For unquaternized resin 1, after swelling, its volume is five timeslarger than before, and can hold water five times more than its ownweight. Other resins, both quaternized and unquaternized, have alsoshown tremendous H₂ O swellabilities.

We claim:
 1. A swellable, covalently cross-linked amine homopolymercomprising functional groups consisting of linear or branched amineshaving the chemical formula ##STR6## and pharmaceutically acceptablesalts thereof having the chemical formula ##STR7## wherein P representsa hydrophilic, covalently cross-linked, non-digestible homopolymerbackbone;R is hydrogen or lower alkyl; X⁻ is a pharmaceuticallyacceptable anion; m is an integer of 1 to 10 inclusive; and n, o and pare, independent from one another, integers of 2 to 12, inclusive. 2.The covalently cross-linked, amine homopolymer of claim 1, having thechemical formula (Ia), and pharmaceutically acceptable salts thereofhaving the chemical formula (Ic), whereinR is hydrogen or methyl; m is1, 2 or 3; and n is 2 or
 3. 3. The covalently cross-linked aminehomopolymer of claim 1, having the chemical formula (Ia), andpharmaceutically acceptable salts thereof having the chemical formula(Ic), whereinP represents a polyacrylamide resin.
 4. The covalentlycross-linked amine homopolymer of claim 1 having the chemical formula(Ib), and pharmaceutically acceptable salts thereof having the chemicalformula (Id), whereinR is hydrogen or methyl; m is 1; and n, o and p areeach
 2. 5. The covalently cross-linked amine homopolymer of claim 1having the chemical formula (Ib), and pharmaceutically acceptable saltsthereof having the chemical formula (Id), whereinP represents apolyacrylamide resin.
 6. A porous, non-digestible, covalentlycross-linked amine homopolymer, comprisingthe covalently cross-linkedhomopolymer of claim 1, wherein P comprises a porous, covalentlycross-linked, non-digestible homopolymer.
 7. The covalently cross-linkedamine homopolymer of claim 1, having the chemical formula

    P--(CH.sub.2).sub.2 NH.sub.2 ;

and protonated and quaternized derivatives thereof having the chemicalformula

    P--(CH.sub.2).sub.2 N.sup.+ H.sub.3 X.sup.- ; and

    P--(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.3 X.sup.- ;

wherein P represents a polyacrylamide resin; and X comprises apharmaceutically-acceptable anion.
 8. The covalently cross-linked aminehomopolymer of claim 1, having the chemical formula

    P--[(CH.sub.2).sub.2 NH].sub.2 H;

and protonated and quaternized derivatives thereof having the chemicalformula

    P--[(CH.sub.2).sub.2 N.sup.+ H.sub.2 ].sub.2 H.2X.sup.- ; and

    P--[(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2 ].sub.2 CH.sub.3.2X.sup.- ;

wherein P represents a polyacrylamide resin; and X⁻ comprises apharmaceutically-acceptable anion.
 9. The covalently cross-linked aminehomopolymer of claim 1, having the chemical formula

    P--[(CH.sub.2).sub.2 NH].sub.3 H;

and protonated and quaternized derivatives thereof having the chemicalformula

    P--[(CH.sub.2).sub.2 N.sup.+ H.sub.2 ].sub.3 H.3X.sup.- ; and

    P--[(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2 ].sub.3 CH.sub.3.3X.sup.- ;

wherein P represents a polyacrylamide resin; and X⁻ comprises apharmaceutically-acceptable anion.
 10. The covalently cross-linked aminehomopolymer of claim 1, having the chemical formula

    P--(CH.sub.2).sub.3 NH.sub.2 ;

and a protonated derivative thereof having the chemical formula

    P--(CH.sub.2).sub.3 N.sup.+ H.sub.3 X.sup.- ;

wherein P represents a polyacrylamide resin; and X⁻ comprises apharmaceutically-acceptable anion.
 11. The covalently cross-linked aminehomopolymer of claim 1, having the chemical formula

    P--(CH.sub.2).sub.4 NH.sub.2 ;

and a protonated derivative thereof having the chemical formula

    P--(CH.sub.2).sub.4 N.sup.+ H.sub.3 X.sup.- ;

wherein P represents a polyacrylamide resin; and X⁻ comprises apharmaceutically-acceptable anion.
 12. The covalently cross-linked aminehomopolymer of claim 1, having the chemical formula

    P--(CH.sub.2).sub.6 NH.sub.2 ;

and a protonated derivative thereof having the chemical formula

    P--(CH.sub.2).sub.6 N.sup.+ H.sub.3 X.sup.- ;

wherein P represents a polyacrylamide resin; and X⁻ comprises apharmaceutically-acceptable anion.
 13. The covalently cross-linked aminehomopolymer of claim 1, having the chemical formula

    P--(CH.sub.2).sub.12 NH.sub.2 ;

and a protonated derivative thereof having the chemical formula

    P--(CH.sub.2).sub.12 N.sup.+ H.sub.3 X.sup.- ;

wherein P represents a polyacrylamide resin; and X⁻ comprises apharmaceutically-acceptable anion.